7-azido-1-(methylsulfonyl)heptan-2-yl ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)(4-(diethylcarbamoyl)phenyl)carbamate | 1346434-72-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 英文名称: 7-azido-1-(methylsulfonyl)heptan-2-yl ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)(4-(diethylcarbamoyl)phenyl)carbamate
• CAS: 1346434-72-7
• 化学式: C₄₃H₅₁N₇O₁₀S
• 分子量: 857.985
• InChiKey: NQDYCYHAQWXKGS-CWXYTELWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.39
• 重原子数：
  61.0
• 可旋转键数：
  18.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  223.4
• 氢给体数：
  1.0
• 氢受体数：
  13.0

反应信息

• 作为反应物：
  描述：

  7-azido-1-(methylsulfonyl)heptan-2-yl ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)(4-(diethylcarbamoyl)phenyl)carbamate 在 溶剂黄146 、 三甲基膦 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Macromolecular Prodrug That Provides the Irinotecan (CPT-11) Active-Metabolite SN-38 with Ultralong Half-Life, Low C_max , and Low Glucuronide Formation

  摘要：

  We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

  DOI：

  10.1021/jm401644v
• 作为产物：
  描述：

  1-(methanesulfonyl)-7-azido-2-heptyl chloroformate 在 吡啶 、 三甲基氯硅烷 、 potassium tert-butylate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 26.25h， 生成 7-azido-1-(methylsulfonyl)heptan-2-yl ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)(4-(diethylcarbamoyl)phenyl)carbamate
  参考文献：
  名称：

  Macromolecular Prodrug That Provides the Irinotecan (CPT-11) Active-Metabolite SN-38 with Ultralong Half-Life, Low C_max , and Low Glucuronide Formation

  摘要：

  We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

  DOI：

  10.1021/jm401644v

文献信息

• [EN] CONTROLLED RELEASE FROM MACROMOLECULAR CONJUGATES<br/>[FR] LIBÉRATION CONTRÔLÉE À PARTIR DE CONJUGUÉS MACROMOLÉCULAIRES
  申请人：PROLYNX LLC

  公开号：WO2011140393A1

  公开（公告）日：2011-11-10

  The invention relates to conjugates of macromolecular carriers and drugs comprising linkers that release the drug or a prodrug through rate-controlled beta-elimination, and methods of making and using the conjugates.

  这项发明涉及大分子载体和药物的共轭物，包括释放药物或前药的连接剂，通过速率控制的β-消除释放药物，以及制备和使用这些共轭物的方法。